Translational Studies of ADAMTS7 a Novel GWAS Locus for Coronary Atherosclerosis

描述（由申请人提供）：动脉粥样硬化性冠状动脉疾病（CAD）仍然是导致死亡和残疾的主要原因。我们需要新的生物学发现来改变我们对这种疾病的认识，并推动临床和治疗的进步。在最近的全基因组关联研究（GWAS）中发现的CAD位点中，许多位点与已知的动脉粥样硬化危险因素或已知机制没有明显的关联。然而，很少有新的基因座在基因座上结合了明确的候选基因，合理的生物学，以及提出特定翻译假设的初步证据。通过GWAS，我们发现并复制了ADAMTS7作为冠状动脉粥样硬化的新位点。这一发现在另外两个大规模GWAS项目中得到了重复。ADAMTS7与传统的危险因素没有关系。然而，这种金属蛋白酶在人血管平滑肌细胞（VSMC）和动脉粥样硬化病变中表达，我们的初步研究表明，Adamts7-/-基因缺失可以降低小鼠体内对股动脉损伤的新内膜反应。我们假设ADAMTS7通过切割软骨寡聚基质蛋白（COMP）促进向VSMC合成表型的转变并加速动脉粥样硬化，COMP是VSMC迁移、增殖和基质分泌的内源性刹车。在这里,我们提出了一系列的实验:(目标1)定义ADAMTS7薪酬结构,发展高通量ADAMTS7试验用于老鼠和人类活动,(目标2)检查的影响生殖功能丧失(LOF)和功能(GOF) ADAMTS7 VSMC表型,血管损伤和动脉粥样硬化小鼠模型,(目标3)查询功能的影响和CAD罕见的协会和低频非同义ADAMTS7等位基因在人类。我们的研究团队有能力开展这些转化性研究，并进一步了解ADAMTS7在动脉粥样硬化中的作用的因果关系、方向性和机制。

DESCRIPTION (provided by applicant): Atherosclerotic coronary artery disease (CAD) remains a major cause of death and disability. New biological discoveries are required to transform our understanding of the disease and to spur clinical and therapeutic advances. Of CAD loci identified through recent genome wide association studies (GWAS), many have no apparent association with established risk factors or known mechanisms of atherosclerosis. Few new loci, however, have the combination of a clear candidate gene at the locus, plausible biology, and preliminary evidence that suggest specific translational hypotheses. Through GWAS, we discovered and replicated ADAMTS7 as a novel locus for coronary atherosclerosis. This finding has been reproduced in two other large-scale GWAS initiatives. ADAMTS7 has no relationship to traditional risk factors. This metalloproteinase, however, is expressed in human vascular smooth muscle cell (VSMC) and atherosclerotic lesions and our preliminary studies suggest that Adamts7-/- gene deletion in mice reduces the in vivo neointimal response to femoral artery injury. We hypothesize that ADAMTS7 promotes transition to VSMC synthetic phenotype and accelerates atherosclerosis by cleaving cartilage oligomeric matrix protein (COMP) an endogenous brake on VSMC migration, proliferation and matrix secretion. Here, we propose a series of experiments to: (Aim 1) define ADAMTS7 structure-function for COMP and develop a high-throughput ADAMTS7 activity assay for use in mouse and human, (Aim 2) examine effects of germline loss-of-function (LOF) and gain-of-function (GOF) of Adamts7 on VSMC phenotype, vascular injury and atherosclerosis in mouse models, and (Aim 3) interrogate functional impact and CAD association of rare and low frequency non-synonymous ADAMTS7 alleles in human. Our investigative team is well positioned to execute these translational studies and advance our understanding of causation, directionality and mechanisms of ADAMTS7 action in atherosclerosis.